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Targeted Therapies in Hematology & Oncology Mark B Juckett MD Section of Hematology/BMT University of Wisconsin
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Classical Drug Discovery
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Targeted Therapy Therapeutics directed at specific molecular “lesions” responsible for carcinogenesis Examples: tyrosine kinase pathway (bcr-abl, PDGF) proteosomal pathways survival signals (MCL1, BCL2) heat shock proteins immunological activation/tolerance
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Chronic Myeloid Leukemia (CML) and Targeted Therapy CML –Cancer of the hematopoietic stem cell –Well-characterized molecular pathogenesis Philadelphia (Ph) chromosome –First abnormality associated with cancer Bcr-Abl tyrosine kinase –A single molecular abnormality that causes transformation of a hematopoietic progenitor into a malignant clone
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Epidemiology of CML Median age range at presentation: 45 to 55 years Incidence increases with age –12%–30% of patients are >60 years old Male-to-female ratio–1.3:1 At presentation –50% diagnosed by routine laboratory tests –85% diagnosed during chronic phase
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CML - Age specific incidence BMT Candidates
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Clinical Course: Phases of CML Chronic phase Median 5–6 years stabilization Accelerated phase Median duration 6–9 months Blast crisis Median survival 3–6 months Advanced phases
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Therapies for Advanced Stages of CML Essentially, NO effective treatment
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Therapeutic Options for CML Allogeneic stem cell transplantation (SCT) Interferon - alpha hydroxyurea (busulfan, 32 P) Imatinib mesylate (formerly STI571)
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Allogeneic Stem Cell Transplant in CML International Bone Marrow Transplant Registry: 1990–1995 HLA = human leukocyte antigen; MUDs = matched unrelated donors. www.bmtinfo.org. Accessed June 11, 2000. HLA-identical siblings MUDs 1234512345 Years From BMT P=.0001 100 80 60 40 20 0 Probability (%) of Leukemia-Free Survival Chronic Phase (N=1756) Chronic Phase (MUD) (N=391) Blast Phase (N=72) Accelerated Phase (N=262) Only Curative Treatment
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IFN- : Clinical Results in CML CHR = complete hematologic response. 1.Kantarjian HM et al. Ann Intern Med. 1995;122:254-261; 2. Ozer H et al. Blood. 1993;82:2975-2984; 3. Mahon F et al. Blood. 1994;84:3592; 4. Hehlmann R et al. Blood. 1994; 84:4064-4077; 5. Italian Cooperative Study Group on CML. N Engl J Med. 1994;330:820; 6. Allan NC et al. Lancet. 1995;345:1392-1397; 7. Ohnishi K et al. Blood. 1995;86:906-916; 8. Silver RT et al. Blood. 1996;88 (suppl 1) 638a; 9. Tura S et al. Blood. 1998;92 (suppl 1) 317a; 10. Guilhot F et al. N Engl J Med. 1997;337:223-229; 11. Kantarjian HM et al. J Clin Oncol. 1999;17:284-292. Complete Cytogeneic response 10 – 15%
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Cytogenetic Response and Survival With IFN- Guilhot F et al. N Engl J Med. 1997;337:223-229. Major response Proportion Surviving 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.01224364860 Minor or no response P <.001 Months After Treatment
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Chemotherapy: Chronic Phase CML Oral cytotoxic agents –Hydroxyurea - standard treatment for rapid control –Busulfan - rarely used, toxic, decreased survival Hematologic response in up to 90% of patients Well tolerated No cytogenetic effects Palliative care—no effect on disease progression
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Cytogenetic Abnormality of CML: The Philadelphia Chromosome Discovered in 1960 by Nowell and Hungerford First consistent genetic “lesion” in human cancer
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The Ph Chromosome: t(9;22) Translocation 22 bcr abl Ph ( or 22q-) bcr-abl FUSION PROTEIN WITH TYROSINE KINASE ACTIVITY 9 9 q+
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p210Bcr-Abl Fusion Protein Tyrosine Kinase Faderl S et al. N Engl J Med. 1999;341:164-172. Extracellular space Y177 BAP-1 GRB2 Cytoplasm SH3 SH2 SH1 CBL SHC CRKL
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bcr-abl Gene and Fusion Protein Tyrosine Kinases Adapted from Melo JV. Blood. 1996;88:2375-2384. p210 Bcr-Abl p185 Bcr-Abl 2-11 Chromosome 9 c-bcr Chromosome 22 c-abl Exons Introns CML Breakpoints ALL Breakpoints 1 2-11
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Bcr-Abl as a Therapeutic Target for CML Bcr-Abl translocation is detected in all patients with CML Bcr-Abl tyrosine kinase is the causative abnormality of CML Bcr-Abl tyrosine kinase is constitutively activated in CML cells, and activation is necessary for growth Inhibitors of Bcr-Abl inhibit the growth of CML cells Imatinib mesylate specifically blocks the function of Bcr-Abl
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Steps to Develop Imatinib mesylate Study and understand the Bcr-Abl tyrosine kinase homologous to abl, PDGF, c-kit proteins Design a molecule that blocks the activation site i.e. the ATP binding site Refine the molecule to enhance specificity Add a chemical group to allow it to work as a pill Test the compound on CML cells in the lab Determine whether it is safe Test the new drug in patients
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Structure of Imatinib Mesylate Class: Phenylaminopyrimidines, 589.7 mw C 29 H 31 N 7 OCH 4 SO 3 CH 3 SO 3 H
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Mechanism of Action of Imatinib Mesylate Goldman JM, Melo JV. N Engl J Med. 344:1084-1086.
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Cellular Selectivity of Imatinib Mesylate: IC 50 M Kinases InhibitedKinases Not Inhibited v-ABL0.1–0.3Flt-3>10 p210Bcr-Abl0.25c-Fms, v-Fms>10 p185Bcr-Abl0.25EGF receptor>100 TEL-Abl0.35c-erbB2>100 PDGF-R0.1Insulin receptor>100 TEL-PDGF-R0.15 IGF-I receptor>100 c-Kit0.1 v-Src>10 JAK-2>100 PDGF-R = platelet-derived growth factor receptor; EGF = epidermal growth factor; IGF-I = insulin-like growth factor-I. Druker BJ et al. Nat Med. 1996;2:561-566.
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Effect of Imatinib Mesylate on Growth of Bcr-Abl–Positive and Bcr-Abl–Negative Cell Lines Gambacorti-Passerini C et al. Blood Cells Mol Dis. 1997;23:380-394. *Bcr-Abl–negative cell lines. † Bcr-Abl–positive cell lines. Imatinib Mesylate Concentration ( M ) U937* KG1* SU DHL1* KCL22 † K562 † KU812 †
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Imatinib Mesylate: Rapid Hematologic Response WBC x 10 3 100 10 1 0306090120150 Days on Imatinib Mesylate
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Imatinib Mesylate: Steady-State Pharmacokinetics Rapidly and completely absorbed after oral administration Absolute bioavailability 98% Terminal half-life (t 1/2 ) 18–22 h; volume of distribution 435 L; and clearance 14 L/h Linear and dose-proportional increase in AUC with doses 25 mg to 1000 mg
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Clinical Trials Phase I Conclusions Well tolerated with a mild side-effects profile In all phases of CML, imatinib mesylate achieved –Hematologic responses –Cytogenetic responses Time to response was rapid
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Phase II Studies With Imatinib Mesylate 3 large international trials have been conducted –0110: Patients with CML in chronic phase after failure of IFN- therapy –0109: Patients with CML in accelerated phase –0102: Patients with CML in myeloid blast crisis Study design and objectives –Open-label, multicenter, noncontrolled –Imatinib mesylate dose: 400 mg to 600 mg –Assess safety, efficacy, and survival rate
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Phase II Study Patients With CML Kantarjian, et al, 2002 Patients with CML Chronic phase after IFN failure Accrual time: December 1999 to May 2000 Patients with CML in chronic phase: – Hematologic failure – Cytogenetic failure – IFN- intolerant Primary endpoint: cytogenetic response NEJM 346:645, 2002
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Chronic Phase: Patient Demographics (n=532) Median age [yrs] (range)57 (18–90) IFN- failure –Hematologic failure152 (29%) –Cytogenetic failure186 (35%) –IFN- intolerance194 (36%) Months from diagnosis (range)32 (3–218) Months of prior IFN- * (range)14 (>1–135) * IFN- at doses >25 MIU/week. NEJM 346:645, 2002
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Cytogeneic and Hematologic Responses NEJM 346:645, 2002 Median time on treatment was 17.5 months
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Time to Progression to Advanced disease Rate of progression-free survival was 89% at 18 months NEJM 346:645, 2002
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Time to Progression According to Cytogenetic Response NEJM 346:645, 2002 Major cytogenetic response includes complete and partial responders
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Prognostic Factors associated with Major Cytogenetic Response Response to interferon therapy Time since diagnosis of CML Presence of anemia at diagnosis Presence of Blasts in peripheral blood Presence of Blasts in the bone marrow NEJM 346:645, 2002
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Adverse Events related to Treatment NEJM 346:645, 2002
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Accelerated Disease Study: Responses Talpaz, et al, 2002 Blood 99: 1928, 2002
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Time to Hematologic and Cytogeneic Response Blood 99: 1928, 2002
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Overall Survival Blood 99: 1928, 2002 P = 0.01
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Blast Crisis Study: Responses Median time to major cytogenetic response was 3 months Most patients treated with 600mg
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Hematologic Response Duration Median duration of response 10 months
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Overall survival (229 pts) Median survival time 6.9 months
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Gleevec vs. Interferon for new CML International Randomized Study – Phase III 1,106 patients, 177 center, 16 countries Gleevec 400 mg/day vs INF 5 MIU/M2/day with Ara-C 20mg/M2/day 10 days per month Median follow-up 14 months
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Gleevec vs. Interferon for new CML Interim analysis presented at ASCO 2002
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Considerations When Using Imatinib Mesylate Imatinib mesylate should be taken with food and a large glass of water Exposure to imatinib mesylate may increase if liver function is impaired Effect of renal or liver insufficiency not well studied Use in pregnancy unknown Potential for drug interactions –P450-CYP3A4 or CYP2D6 inhibitors and substrates
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Cytochrome p450 - CYP2D6 Substrates Amitriptyline captopril Beta-blockers Morphine derv. Cyclophosphamide Antiarrhythmics Tamoxifen Nicotine Inhibitors Amiodarone Celecoxib Chlopromazine Cimetidine Fluoxetine Ritonavir Valproic acid Methadone Substrates - concentration increases when given with Gleevec Inhibitors - concentration of Gleevec increases when given with Inhibitor
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Cytochrome p450 - CYP3A4 Substrates Acetaminophen Amiodarone Nifedipine Cyclosporin Corticosteroids Warfarin Cannabinoids Estradiol Pantoprazole Inhibitors Amiodarone Azithromycin Cyclosporine Metronidazole Itraconazole Ranitidine Troglitazone Substrates - concentration increases when given with Gleevec Inhibitors - concentration of Gleevec increases when given with Inhibitor
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Imatinib Mesylate—Use in CML Practical Considerations
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Imatinib Mesylate: Dosing In chronic phase CML –400 mg once daily In advanced phase CML –600 mg once daily Imatinib mesylate is supplied as 100-mg capsules Dose escalation (400 mg to 600 mg or 600 mg to 800 mg) may be considered: –Disease progression –Failure to achieve a hematologic response after at least 3 months –Loss of a previously achieved hematologic response
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Conclusions: Imatinib Mesylate in CML Therapy specifically designed to target the molecular cause of CML –Potent and selective inhibitor of Bcr-Abl Improved rates of hematologic and cytogenetic responses in all stages of disease Encouraging survival and time to progression - so far Survival compared to IFN unknown Favorable side-effects profile (compared to IFN) Convenient once-daily oral dosing (but $$$)
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Imatinib Mesylate use in Solid Tumors Additional molecular targets –c-Kit –PDGF-R Relationship to prognosis and malignant transformation is unknown Tumors associated with these targets –Sarcomas –Lung cancer –Prostate cancer –Gliomas and neuroblastoma –Breast cancer –Seminomas and germ-cell tumors Evidence for mutations leading to constitutive activation
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KIT Expression in Human Malignancies JCO 20:1692, 2002
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Tyrosine Kinase Inhibitors to KIT
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Gastrointestinal Stromal Tumors (GIST) Infrequent tumor (~0.2% of all GI tumors) Occur primarily in stomach (60%–70%) and small intestine Therapeutic options – Surgery was only effective modality – Few respond to chemotherapy Outcomes – For unresectable/metastatic disease Estimated time to progression <2 months Estimated survival <1 year
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Distinguishing GIST from sarcomas is difficult Arise from GI mesenchymal stem cells Gain-of-function mutations in c-kit appear to be the most important alteration leading to the formation of GIST Abnormal KIT signaling in GIST may be the result of genetic mutations in the DNA of the c-kit gene GIST cells are positive for KIT (CD117) in 100% of cases Pathology of GIST
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Microscopic Appearance of GIST H+E StainCD117 (c-kit) Stain GIST Normal Small Intestine
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Normal Functions of c-KIT KIT is tyrosine kinase found in many normal tissues and is essential for Hematopoiesis (blood cell development) Melanogenesis (development of skin pigmentation) Fertility Activation of KIT plays a critical role in different cell functions Proliferation (cell multiplication) Differentiation (cell maturation) Apoptosis (programmed cell death) Adhesion (cell attachment)
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June 27, 2000 October 4, 2000 3 March 20005 April 2000 First GIST Patient After 4-Week Treatment With Imatinib Mesylate Joensuu et al. N Engl J Med. 2001;344:1052-1056.
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EORTC Phase I Study of Imatinib mesylate Primary objective: Establish a maximum tolerated dose (MTD) for GIST patients Secondary objective: Determine efficacy 40 patients, 36 with documented GIST Dose administered at 400mg daily and increased by 200mg increments, up to 1000mg Proc ASCO 20:1a, abst 2, 2001
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MTD = 800mg daily dose with 1000mg leading to DLT’s Objective Response = 69.4% PR = 52.7% SD = 16.7% Adverse events (AEs) were mild to moderate in severity Most patients experienced relief of symptoms after one week of treatment EORTC Phase I Study: Results Proc ASCO 20:1a, abst 2, 2001
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Phase II Study: Objectives Primary objective: assessment of clinical and biologic activity in GIST patients Secondary objectives: Time to onset of response Duration of response Time to treatment failure JCO 20:1a, abst1, 2001
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Phase II Study: Patient Characteristics n (%) Total147 (100) Age - median54 (18–83) ECOG PS 062 (42) Recurrent tumor132 (90) Liver115 (78) Peritoneum56 (38) Retroperitoneum21 (14) Previous therapy Surgery144 (98) Chemotherapy75 (51) JCO 20:1a, abst1, 2001
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Phase II Study: Best Confirmed Responses All Doses (N=147) 400mg n=73 600mg n=74 Best Response Complete response (CR)0 Partial response (PR)40% Stable disease (SD)41% Progressive disease (PD)12% Not evaluable5% JCO 20:1a, abst1, 2001
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